Melatoninand Reproduction

A major physiological role of melatonin in adult mammals is the regulation of seasonal reproduction (for reviews see 3,21,33,68 and this volume). The pineal gland is necessary for appropriate perception of seasonal changes in day length and thus for the proper timing of reproduction in species which breed seasonally. The duration of the nocturnal melatonin elevation is regulated by the photoperiod. Melatonin ultimately affects reproductive activity by modulating the activity of hypothalamic neuroendocrine circuits whose activity is necessary for gonadal function. In the broadest

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Figure 2. The maternal pineal gland is the source of melatonin rhythms in fetal sheep. Top panel: Melatonin rhythms in the mother and fetus are similar in phase and amplitude. Lower panel: Removal of the maternal pineal abolishes maternal and fetal melatonin rhythms. Modified from Ref. 87.

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Figure 2. The maternal pineal gland is the source of melatonin rhythms in fetal sheep. Top panel: Melatonin rhythms in the mother and fetus are similar in phase and amplitude. Lower panel: Removal of the maternal pineal abolishes maternal and fetal melatonin rhythms. Modified from Ref. 87.

sense, then, melatonin broadly influences development by restricting the season of conception, and thus the season of birth, such that the offspring are born at a season with the most favorable environmental conditions possible.

The influence of melatonin on reproductive development begins during the prenatal period and extends into postnatal life. The following sections will detail the influence of melatonin on reproduction during development.

3.1. Postnatal Photoperiod and the Timing of Puberty

In many seasonally breeding species, the timing of initial reproductive development (puberty) is strongly influenced by daylengths experienced during the postnatal period. The most well-studied species include Siberian hamsters and sheep (for reviews see 3,21). Administration of melatonin in the appropriate temporal (durational) patterns can influence the timing of puberty in these species. In Siberian hamsters, for example, exposure to long days stimulated postnatal reproductive development. Infusion of long-day patterns of melatonin similarly stimulates gonadal growth, while short-day patterns of melatonin suppress puberty (8; Figure 3). While the details are species-specific, the same general phenomenon exists in other photoperiodic species: specific photoperiodic requirements must be met to allow rapid pubertal development, and these photoperiodic requirements are transduced to the neuroendocrine axis by melatonin (21,29,63,83,85,87). Melatonin implants alter the timing of pubertal development in many photoperiodic species, likely by preventing accurate perception of the environmental daylength normally imparted by the melatonin rhythm.

In Syrian hamsters, initial reproductive development is not influenced by daylength or melatonin. Syrian hamsters detect daylengths and melatonin prior to puberty, but the response is delayed until after puberty due to a long latency to respond (57).

Correlation between a developmental decline in melatonin levels with the timing of puberty in humans led to speculation that melatonin regulates the timing of puberty (72). Subsequent investigation indicates that this developmental decline in melatonin levels is due at least in part to developmental changes in body mass (and thus volume

Figure 3. Postnatal photoperiod and melatonin influence the rate of reproductive development in Siberian hamsters. Top panel: Pineal-intact juvenile males were housed in photoperiods ranging from constant light to 10 hours light: 14 hours darkness beginning at 18 days of age. Lower panel: Juvenile male hamsters were pinealectomized at 18 days of age and received infusions of melatonin (10 ng per night) each night from day 18 to day 30. All animals were born to pineal-intact dams housed in 16 hours of light per day. Testicular weights were assessed at 30 days of age. Long nightly melatonin infusions mimicked the effect of exposing males to short days, and the duration-response curves for melatonin and darkness are parallel. Data from Ref. 8.

Figure 3. Postnatal photoperiod and melatonin influence the rate of reproductive development in Siberian hamsters. Top panel: Pineal-intact juvenile males were housed in photoperiods ranging from constant light to 10 hours light: 14 hours darkness beginning at 18 days of age. Lower panel: Juvenile male hamsters were pinealectomized at 18 days of age and received infusions of melatonin (10 ng per night) each night from day 18 to day 30. All animals were born to pineal-intact dams housed in 16 hours of light per day. Testicular weights were assessed at 30 days of age. Long nightly melatonin infusions mimicked the effect of exposing males to short days, and the duration-response curves for melatonin and darkness are parallel. Data from Ref. 8.

of distribution), and is without a strict relationship to pubertal development (9,48,88). While endogenous melatonin does not appear to play a role in timing human puberty, no data are available to draw a conclusion with respect to the effects of exogenous melatonin on puberty in humans.

3.2. Prenatal Programming of Postnatal Reproductive Development

Photoperiodic information reaches the fetus during prenatal life, and can have a dramatic impact on reproductive development (For reviews see 14,77). The initial observation that day lengths experienced during the prenatal period affect pubertal development began with studies of montane voles (Microtus montanus) conducted by Teresa Horton. Field work had shown that male voles born after the summer solstice were unlikely to undergo rapid reproductive development, and these late-season males would often delay puberty until the following Spring. This seemed contrary to photoperiodic mechanisms, as the day length just after the summer solstice is among the longest of the year. Horton's laboratory studies revealed that the photoperiod experienced during prenatal life affected the timing of postnatal reproductive development (25,26). Cross-fostering studies revealed that the effect of daylength was perceived during the prenatal period (27).

Subsequent studies have primarily focused on Siberian hamsters, with several groups demonstrating that prenatal photoperiod influences postnatal reproductive development (Figure la; Figure 4 top; see 77 for review). Pups reared in an

Figure 4. The prenatal photoperiod and prenatal exposure to melatonin influence the rate of reproductive development in male Siberian hamsters.All offspring were reared in a 14 hour light : 10 hour dark (14 L : 10D) lighting cycle after birth, and paired testis weights were determined at euthanasia on postnatal day 34. Values represent mean ± SEM. Sample sizes are indicated within each bar. A. Prenatal perception of day length by offspring of pineal intact-dams. Animals experiencing a decrease in daylength from 16L :8D to 14L : 10D at birth have slower reproductive development than hamsters maintained in the intermediate 14L : 10D photoperiod throughout pre- and postnatal development. B. Maternal pinealectomy prior to breeding prevents fetal perception of daylength. C. Melatonin communicates daylength information to the fetus. The nightly duration of infusion of melatonin was varied (50 ng in 0.2 cc delivered over 6 or 8 hours per night, for 3-7 nights at the end of gestation) to reproduce melatonin pattern that would occur in pineal-intact hamsters maintained in photoperiods of 16L : 8D or 14L : 10D, respectively. The effects of varying melatonin infusion duration mimicked the effects of varying prenatal photoperiod. Modified from Ref. 77.

Figure 4. The prenatal photoperiod and prenatal exposure to melatonin influence the rate of reproductive development in male Siberian hamsters.All offspring were reared in a 14 hour light : 10 hour dark (14 L : 10D) lighting cycle after birth, and paired testis weights were determined at euthanasia on postnatal day 34. Values represent mean ± SEM. Sample sizes are indicated within each bar. A. Prenatal perception of day length by offspring of pineal intact-dams. Animals experiencing a decrease in daylength from 16L :8D to 14L : 10D at birth have slower reproductive development than hamsters maintained in the intermediate 14L : 10D photoperiod throughout pre- and postnatal development. B. Maternal pinealectomy prior to breeding prevents fetal perception of daylength. C. Melatonin communicates daylength information to the fetus. The nightly duration of infusion of melatonin was varied (50 ng in 0.2 cc delivered over 6 or 8 hours per night, for 3-7 nights at the end of gestation) to reproduce melatonin pattern that would occur in pineal-intact hamsters maintained in photoperiods of 16L : 8D or 14L : 10D, respectively. The effects of varying melatonin infusion duration mimicked the effects of varying prenatal photoperiod. Modified from Ref. 77.

"intermediate" postnatal photoperiod differ in their rate of reproductive development if the prenatal photoperiods experienced by their mothers differed (63,64,75). At more extreme photoperiods, the postnatal photoperiod "overrides" the influence of the prenatal photoperiod (63,65). The influence of prenatal daylength occurs prenatally (6.5). Considering the role of the pineal gland in photoperiodic regulation, it seemed likely that removal of the maternal pineal gland would prevent prenatal perception of daylength. Several groups have shown that the maternal pineal gland is necessary for prenatal communication of daylength information (29,75; Figure 4 center). To specifically assess the role of melatonin, we delivered infusions of melatonin into pinealec-tomized dams during pregnancy. Timed infusions of melatonin were delivered for the last several nights of gestation, with melatonin infusion duration (e.g., the hours of infusion per night) being varied to mimic the physiological pattern of the hormone that would occur under various lighting schedules. The nightly duration of melatonin exposure during gestation determined the rate of pubertal development (75,79; Figure 4 lower). Infusions delivered during the day and during the night appeared equally effective; the important variable was the infusion duration. In a subsequent study, we restricted the number of infusions to determine the time of peak sensitivity to mela-tonin, and also to define the minimum stimulus. A single gestational melatonin infusion did not influence postnatal reproductive development, but two infusions on consecutive nights did provide a sufficient signal (79). A period of maximum sensitivity to melatonin infusions occurs during late gestation. Studies using timed injection of melatonin (rather than infusions) support the conclusion that melatonin is a critical cue for transfer of day length information to the fetus (28,65). In keeping with the historical theme of this conference, it is worth noting that our desire to identify sites of melatonin action within fetal hamster brain prompted our first studies of melatonin receptor localization (80). Our melatonin receptor work recently led to our identification of a family of melatonin receptor subtypes (see 54 for review).

Maternal transfer of photoperiodic information has been referred to as "prenatal programming" of postnatal reproductive development, as the influence of the prenatal photoperiod can be observed in animal reared in constant light, in the absence of postnatal melatonin exposure (28,65).

One way to interpret these data, and the field data from voles, is that the developing animal takes a reading of daylength (melatonin duration) during late fetal life and compares this with the melatonin signal derived from the developing pineal around 15-20 days of age (67). This model suggests that a postnatal melatonin pattern is interpreted differently depending on an animal's prenatal photoperiodic history. Shaw and Goldman (62) have reported that the response to postnatal melatonin infusions is in fact not dependent on the prenatal photoperiod; reproductive response to postnatal melatonin infusions was dictated solely by infusion duration, without an influence of the prenatal photoperiod. Assessment of the melatonin rhythms in populations of juvenile hamsters with different prenatal photoperiodic histories revealed a difference in the duration of the nocturnal melatonin elevation (61). These results suggest a model in which the effect of prenatal photoperiod is to alter the SCN-generated pattern of postnatal melatonin production, rather than having an effect on programming neuroendocrine function per se. This model is unable to account for the impact of prenatal photoperiodic history on animals reared in constant light, in the absence of postnatal photoperiodic information (cf. 28,65).

Finally, Horton et al. (30) have proposed that there are other signals, besides melatonin, involved in the prenatal communication of daylength information in Siberian hamsters. Pregnant hamsters treated with melatonin-containing implants that "swamped out" the endogenous melatonin profile were still able to communicate day length information to their fetuses. Thus, while the pineal gland is necessary for prenatal communication of daylength information (75), and melatonin is sufficient (65,75,79), additional pineal-derived signals may be involved.

The prenatal influence of melatonin on development is not limited to Siberian hamsters and montane voles. Lee, Zucker and colleagues have shown that perinatal development of meadow vole pups (Microtus pennsylvanicus) is influenced by prenatal photoperiod and prenatal melatonin treatment (35-37). Remarkably, there is also an influence of the duration the mother has been exposed to short day lengths, e.g., time since exposure to short days (35,36).

Melatonin influences other neuroendocrine parameters in developing animals prior to puberty, For example, prolactin levels in adult and neonatal sheep are regulated by daylength (20,21). Prolactin levels of fetal sheep are influenced by the pho-toperiod the mother experienced during gestation, with long days resulting in higher prolactin levels (20). Melatonin implants reduce prolactin levels in fetal sheep (4,39). Melatonin acts via the pars tuberalis to influence prolactin secretion in adult sheep (31,44). The same mechanisms appears to be operative in the fetal lamb (46). There is also an influence of photoperiodic history on prolactin: prolactin levels in neonatal lambs exposed to 12 hours of light per day following birth are strongly influenced by the prenatal daylength (20). Photoperiodic history influences prolactin secretion even in fetal sheep (31).

3.3. Seasonal Embryonic Diapause

A fascinating, ecologically important role for melatonin in regulating reproduction during early fetal development is in the initiation and maintenance of seasonal embryonic diapause (for review, see 58). Following fertilization, the blastocyst develops for several days and then "arrests" for a variable period (Figure 5). Implantation and reactivation of development occur such that offspring are born in Spring, with the most favorable conditions for survival. The period of delayed implantation (embryonic diapause) is regulated by the environmental lighting cycle, via melatonin. Season embryonic diapause occurs in many different mammalian species including mustelids (e.g., skunks, ferrets, badgers, weasels, mink), pinipeds (e.g., Australian sea lions and Antarctic fur seals, harbor seals), insectivores (several bat species), canids (wolves and coyotes) bears, and marsupials.

Western spotted skunks, tammar wallabies, and mink have been studied most extensively with respect to the role of the pineal and melatonin. In each of these three species, pinealectomy or denervation of the pineal prevents seasonal embryonic diapause, and melatonin treatment influences the length of diapause (6,7,40,41,45,49). The data from all species are consistent with the interpretation that melatonin acts in the pregnant mother to influence neuroendocrine function, particularly prolactin secretion, and that diapause is caused by alterations in the uterine environment. Melatonin does not appear to directly affect the embryo.

In skunks, melatonin treatment delays implantation by several months, and causes a long-term suppression of prolactin levels. Destruction of the SCN does not block the effect of exogenous melatonin (6). In contrast, anterior hypothalamic lesions disinhibit prolactin production and result in precocious termination of diapause, regardless of the

Figure 5. Schematic representation of seasonal embryonic diapause. A period of embryonic diapause (stippled bar) interrupts fetal development (open bar) for each species. In wallabies, the initial period of diapause is induced by suckling stimuli from the pouch young and is termed lactational diapause (cross-hatched bar) (cf. Ref. 49). The upper portion indicates the annual change in day length at a mid-temperate (ca. 45°) latitude; note that annual day length variation at more polar latitudes would be more extreme than shown. Data are presented relative to solstices to allow presentation of species from both Northern and Southern hemispheres.

Figure 5. Schematic representation of seasonal embryonic diapause. A period of embryonic diapause (stippled bar) interrupts fetal development (open bar) for each species. In wallabies, the initial period of diapause is induced by suckling stimuli from the pouch young and is termed lactational diapause (cross-hatched bar) (cf. Ref. 49). The upper portion indicates the annual change in day length at a mid-temperate (ca. 45°) latitude; note that annual day length variation at more polar latitudes would be more extreme than shown. Data are presented relative to solstices to allow presentation of species from both Northern and Southern hemispheres.

melatonin milieu (7,32). It is not clear whether melatonin acts within or through the anterior hypothalamus; the anterior hypothalamus may be a leg in the final common pathway in prolactin regulation downstream of the melatonin target sites. Considering that high-affinity melatonin receptor binding is restricted to the pars tuberalis in skunks (18), these data suggest a model in which melatonin regulates production of a factor from the pars tuberalis that influences prolactin secretion. A similar proposal has been made to explain the influence of melatonin, mediated by the pars tuberalis, on prolactin secretion in sheep (39). For further discussion of the pars tuberalis as a site of melatonin action, see the chapter by P.J. Morgan (this volume).

3.4. Melatonin and Embryonic Survival

Melatonin is generally viewed as remarkably non-toxic (see 66,73), and this also appears to be the case during fetal life. Melatonin is without effect on development of mouse embryos in vitro (42). A second study reports that melatonin does have toxicity to embryos (10), but the concentrations of melatonin used were 100-200 ug/ml (ca. 0.5-1.0 mM), astronomically high when compared to endogenous melatonin levels (<1 nM) or with the micromolar levels which result following pharmacological doses.

An influence of melatonin injection on embryonic survival has been reported in meadow voles (22). Melatonin injections (10 ug, 2hr before lights off in 14L :10D) reduced survival rates of female (but not male) pups when given prior to blastocyst implantation. Injections later in gestation were without effect. This effect of melatonin may underlie seasonal changes in litter size, and perhaps seasonal changes in sex ratios. The mechanism by which melatonin modulates prenatal mortality in a sex-specific manner is not known.

Getting Back Into Shape After The Pregnancy

Getting Back Into Shape After The Pregnancy

Once your pregnancy is over and done with, your baby is happily in your arms, and youre headed back home from the hospital, youll begin to realize that things have only just begun. Over the next few days, weeks, and months, youre going to increasingly notice that your entire life has changed in more ways than you could ever imagine.

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